Blood bag for lyophilization

ABSTRACT

A lyophilization bag is provided in which a fluid, such as blood, ay be introduced, lyophilized without collapsing the bag, stored, reconstituted and distributed from the bag without intermediate transfer of the useful contents from the bag.

This invention relates to a bag for use in the lyophilization(freeze-drying) of a fluid, particularly blood and red blood cells fortransfusion, and which can also be used for storage and reconstitutionof the lyophilized product. The blood bag for lyophilization accordingto this invention can also be used for the lyophilization, storage, andreconstitution of blood substitutes, such as liposome encapsulatedhemoglobin (hemosome) solutions and cell-free hemoglobin solutions;fluid blood components, including serum and fractions derived fromserum; or any protein-containing solution or suspension.

BACKGROUND OF THE INVENTION

There are several practical problems which are encountered in thelyophilization, storage and reconstitution of fluid products,particularly blood. One of the objects, particularly in dealing withblood or other medical products, is to handle the blood as little aspossible to minimize exposure to sources of possible contamination.Furthermore, the blood should be able to be conveniently stored in itslyophilized state in a sterile environment and then reconstituted withas little handling as possible and with minimal exposure to possiblesources of contamination.

There is the practical problem of conservation of storage space. Itwould be desirable to have the container in which the blood is storedtake up the minimum amount of room, since in many instances, it isstored in a controlled temperature environment, such as a refrigerator,in which space is limited.

Another problem is that the container for the blood must not only besusceptible to sterilization, but must also mechanically withstand lowtemperatures, particularly, for example, liquid nitrogen temperatures,used for lyophilization processes, and withstand application of avacuum.

To minimize storage utilization, the above requirements suggest the useof a flexible, collapsible container. On the other hand, if the contentsof the bag are to be lyophilized under vacuum, the bag must be able towithstand application of a vacuum without collapsing duringlyophilization.

It is thus an object of the present invention to provide alyophilization bag which can be used during lyophilization, thencollapsed to conserve space during storage, which is versatile enough toallow one to reconstitute the contents within the bag so that they maybe used directly from the bag, which will provide a fully-enclosedsterile container system. Thus, according to the invention, the samecontainer may be used for lyophilization, storage and reconstitution,thus avoiding transfers of the contents for these purposes.

This and other objects of the invention will be apparent from thefollowing description and accompanying drawings and appended claims.

SUMMARY OF THE INVENTION

The present invention provides a collapsible, flexible plastic bagcomprising an upper wall and a lower wall sealed to a peripheral sidewall. The upper wall has a major port adapted with a sealable conduit,and the side wall has at least one side port adapted with sealing meansand located approximate to the upper edge of the side wall. The sidewall and upper wall are adapted with a securing means to receiveremovable reinforcing members to restrain the respective walls fromflexing and collapsing the bag. The lower wall has a securing means toaccommodate a removable lowering reinforcing member, which member isalso made of a thermally conducting material to permit cooling of thecontents of the bag through the bottom wall. The bag is also adaptedwith an attachment means for suspending the bag in a position whereby atleast one of the side ports is at a location for withdrawing the fluidcontents from the bag.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a perspective view of the preferred embodiment of alyophilization bag according to the present invention.

FIG. 2 is a partial cross-section view through section line 2--2 of FIG.1 of a side wall, reinforcing member and a securing flap therefor.

FIG. 3 is a perspective view of the lyophilization bag of FIG. 1suspended in a position for withdrawing the liquid contents therefromthrough one of the side ports.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to FIG. 1 there is shown a bag 10 made of a flexible plasticmaterial. The preferred material is a polymeric substance comprisingpolyvinylchloride film plasticized with plasticizer, such aspolyvinylchloride Grade 6 (made by Ellay, Inc., Commerce, Calif. Asshown, the bag comprises an upper wall 11 and a lower wall 12 which areperipherally bonded to a peripheral wall 13. As shown, the bonded edgesbetween the upper wall 11 and the lower wall 13 and, between the lowerwall 12 and peripheral wall 13 may be made by heat or radiofrequencysealing the edges of the walls. However, any equivalent means of sealingthe walls together to form the bag may be utilized. The upper wall 11accommodates a port 14 which, as shown, is approximately centrallylocated on upper wall 11. To the port 14 is affixed conduit 15, at oneend of which is fitted a removable sealing plug 16. In an alternateembodiment the conduit 15 may be omitted and the port 14 may be directlysealed with a removable plug similar to that shown as 16. At one end ofthe peripheral wall 13 there is shown a plurality of sealable side ports17A and 17B. These ports are also affixed with plastic adapters such aspolyethylene similar to port 14. The side ports 17A and 17B, as shown,are located proximate to the upper edge of the juncture between theperipheral wall 13 and upper wall 11 so as to avoid plugging of theseports by any material within the bag 10 when the bag is partially filledwith a liquid or other fluid substance while it rests flat on bottomwall 12 on a level surface.

On the side of the bag 10 opposite to the ports 17A and 17B is located atab 18 which, as shown, is bonded to the upper edge of upper wall 11.Tab 18 accommodates a plurality of orifices 19 from which the bag 10 canbe suspended, as further described hereinbelow in connection with FIG.3. Since bag 10 is made of a flexible material, the bag would becollapsible, if not reinforced. Accordingly, as shown in FIG. 1, thereis shown on upper wall 11 loops which are bonded to the upper wall 11which retain reinforcing inserts 21. The reinforcing inserts 21 may bemade of rigid or semi-rigid material, such as polyethylene, ofsufficient strength to prevent collapsing of bag 10, and in particular,to prevent collapsing of upper wall 11 when a vacuum is applied to theinterior of bag 10 by withdrawal of gas and other vapors through port14. The inserts 21 need only be of sufficient strength to prevent thecollapse of wall 11 when vacuum pressures normally used inlyophilization processes are applied within the bag 10.

Similarly, to prevent collapse of peripheral wall 13 loops 22 and 23 areaffixed to the peripheral wall 13. As shown, a single reinforcing insert24 is utilized, which is inserted into loops 22 and 23 and correspondingloops (not shown) on the sides of the peripheral wall 13 which cannot bedirectly viewed in FIG. 1. A single reinforcing insert 24 isappropriately bent to accommodate the corners of the bag when insertedthrough loops 22 and 23. The reinforcing insert 24 may be made of thesame rigid or semi-rigid polyethylene material as inserts 21.

The bottom wall 12 of bag 10 may also be bonded, preferably on three ofits edges, to an exterior flap to form a pocket (not shown) to receive alower reinforcing member (not shown) to support bottom wall 12. Anyconvenient configuration for supporting a rectangular reinforcing memberon the exterior of wall 12 may be utilized. Instead of a semi-rigidplastic insert, however, the reinforcing member for bottom wall 12 ispreferably a copper plate of a size approximately coextensive with thewall 12. The copper plate will serve as a thermal conductor when the bagis cooled to conduct heat away from the contents of the bag, which liealong the bottom of the bag 10, to assist in cooling during the initialfreezing of the liquid, and then during subsequent lyophilization. Afterlyophilization the reinforcing copper plate may be removed, so theflexible bag may be more conveniently stored, and also to conservecopper plates and reduce the overall weight of the bag and its driedcontents.

The seal to port 17A may be sealed until use. Similarly, port 17B andplug 16 are sealed until use.

Referring to FIG. 2 there is shown a partial cutaway detail ofperipheral wall 13, reinforcing insert 24 and retaining loop 23 alongline 2--2 of FIG. 1. As shown in FIG. 2, the wall 13 is supported fromcollapsing by reinforcing insert 24 which is retained in position byloop 23. The bag is not filled to its fullest extent so that the liquidor other contents 30 of the bag leave an airspace 31 within the bag soas not to plug ports 17A, 17B and 14 when the bag is lying flat onbottom wall 12.

Referring to FIG. 3, there is shown use of bag 10 subsequent toreconstitution of its contents (preferably lyophilized blood or redblood cells), whereby the liquid contents may be drained through eitherof the ports 17A or 17B. Bag 10 is suspended from hook 41 through one ofthe orifices 19 in tab 18.

In the preferred method of using bag 10, after inserting the reinforcinginserts, including the reinforcing and thermoconducting copper platealong bottom wall 12, the plug 16 from the major port 14 is unsealed andadapted with a sterile filter (not shown in FIG. 1). One of the ports(17B) is then unsealed and affixed with a conduit for filling the bagwith its liquid contents to be lyophilized. Hereinafter the contentswill be described as being blood.

The bag 10 is filled to a level below ports 17A and 17B and the port 17Bis resealed or the conduit thereto is closed by an appropriate valve orother means.

The entire bag 10 is then placed within a lyophilizer, the contents arefrozen and lyophilized. Cooling of the contents of the bag is assistedthrough the copper plate (not shown) on the exterior of the bottom ofthe bag. The vapor is removed through port 14 (unsealed), plug 16 and asterile filter (not shown). The bag is prevented from collapsing by thereinforcing inserts 21 (and 24) and the copper plate. Upon completion oflyophilization, the vacuum in the lyophilizer is released by ventingwith sterile, dry inert gas such as nitrogen. The vacuum inside theblood bag is thereby replaced with inert gas via port 14 (unsealed),plug 16 and the attached sterile filter (not shown). The bag is thenremoved from the lyophilizer and conduit 15 is sealed and may be cut toremove excess tubing, plug 16 and the sterile filter. This creates afully sealed sterile environment for storage of the dry product in theclosed bag under a dry inert gas. The copper plate is then removed fromthe exterior of bottom wall 12. If desired, the inserts 24 and 21 mayalso be removed. The bag and its lyophilized contents may then be storedunder a range of temperatures, from -80° C. to +25° C. (roomtemperature), and even in excess of normal room temperatures.

When the contents of the bag are to be reconstituted, port 17B and (17A,if needed) may be unsealed and used for entry and withdrawal forappropriate reconstitution fluids. To use the reconstituted fluids inthe bag, the bag is suspended, preferably as shown in FIG. 3, and itscontents are withdrawn through one or more of the ports 17A or 17B.

It should be apparent in FIGS. 1 and 3 that while only two side ports17A and 17B are shown, the bag may be manufactured with as many ports asdesired.

A particular advantage of the bag according to the present invention isthat it conserves space before use since it may then be collapsed tovirtually a flat piece before the reinforcing inserts are inserted. Thebag may then be filled, used in a lyophilizer, stored, used forreconstitution, and then drained of its contents, without evertransferring the desirable contents from the bag.

It will also be realized that means other than by tab 18 and orifices 19may be utilized to suspend the bag, such as by loops, hooks, etc.

It will also be realized that after lyophilization is complete the bagis sealed to create a self-contained environment suitable for storage ofthe dried contents. Removal of excess tubing, plugs, and appendedsterile filter after sealing of the bag, as well as removal of allcopper plates and semi-rigid wall supports will also serve to reduce thefinal weight of the sealed bag and its contents. It will be realizedthat conservation of weight per sealed bag offers important storage andtransport advantages.

We claim:
 1. A flexible plastic bag comprising an upper wall and lowerwall, said walls sealed at their edges to a peripheral side wall tothereby define the inner volume of said bag;a major port in said upperwall approximately centrally located in said upper wall, said major portadapted with a sealable conduit; at least one side port in said sidewall, said side port adapted with sealing means and said side portlocated proximate to the upper edge of said side wall; securing means onsaid peripheral side wall adapted to receive removable rigid orsemirigid reinforcing members to restrain said side wall from collapsewhen said reinforcing members are secured to said side wall; securingmeans in said upper wall adapted to receive removable rigid orsemi-rigid reinforcing members to restrain said upper wall from collapsewhen said reinforcing members are secured to said upper wall; securingmeans on said lower wall adapted to receive removable semi-rigid orrigid lower reinforcing means, wherein said lower reinforcing meanscomprises a thermoducting material to facilitate conduction of heat toor from the contents of said bag through said lower wall; and attachmentmeans for suspending said bag in a position whereby at least one of saidside ports is at a location for withdrawal of any fluid contents fromsaid bag.
 2. A bag according to claim 1 wherein said sealable conduit isadapted with a sterile filter.
 3. A bag according to claim 1 comprisingat least two of said side ports.
 4. A bag according to claim 1 whereinsaid securing means on said peripheral side wall and on said upper wallcomprise loops adapted to receive said reinforcing members in the formof strips.
 5. A bag according to claim 1 wherein said securing means onsaid lower wall comprises a flexible plastic sheet sealed on three edgesto said lower wall and to said peripheral wall, thereby forming anexterior open-ended pocket with said lower wall.
 6. A lyophilizationplastic bag comprising a flexible plastic bag according to claim 1, andsaid rigid or semi-rigid reinforcing strips retained by said loopsagainst said upper wall and peripheral wall.
 7. A lyophilization bagaccording to claim 6 further comprising a thermally conducting metalplate accommodated by said pocket on said lower wall.
 8. Alyophilization bag according to claim 7 wherein said metal platecomprises copper.
 9. A method for lyophilizing a fluid productcomprising the steps of:(a) providing a container according to claim 1adapted with said reinforcing members in said peripheral wall and upperwall and with said lower reinforcing members in lower wall, and with asterile filter on said sealable conduit; (b) positioning said bag fromstep (a) in a lyophilizer whereby said lower wall is downwardly facing;(c) introducing said fluid product through at least one of said sideports into said bag to a level at which said major port is incommunication with the vapor space within said bag not occupied by saidfluid product; and resealing said port; (d) freezing and lyophilizingthe contents of said bag whereby vapors are withdrawn from said bagthrough said major port, conduit and filter; (e) backfilling said bagwith sterile dry inert gas and withdrawing said bag from saidlyophilizer; and (f) sealing said sealable conduit.
 10. A methodaccording to claim 9 wherein said fluid product comprises blood.
 11. Amethod according to claim 9 wherein said fluid product comprises redblood cells for transfusion.
 12. A method according to claim 9 furthercomprising the step (g) of introducing at least one sterilereconstitution solution into said bag through at least one of said sideports to produce a rehydrated sterile solution suitable for subsequentpharmaceutical use.
 13. A method according to claim 9 wherein said fluidproduct comprises blood components prepared from whole blood, to includeserum or blood protein fractions derived from serum.
 14. A methodaccording to claim 9 wherein said fluid product comprises aprotein-containing solution.